The inhibitory effect of the phenylalkylaminetype Ca2+-entry blocker, tiapamil, on the fast Na+inward current was investigated in guinea-pig papillary muscles by measuring the maximum upstroke velocity (dV/dt)maxof transmembrane action potentials. Tiapamil inhibited (dV/dt)maxat concentrations above 10-6M, with an IC50value of 7 x 10-5M(1 Hz stimulation frequency, 5.9 mMextracellular K+). Verapamil was less potent in depressing upstroke velocity. Inhibition of thedVldtmaxstrongly depended on the frequency at which the muscles were stimulated (“use-dependent” effect). There was no evidence that tiapamil acts in a potential-dependent manner like local anesthetics. The results indicate that the Ca2+-entry blocker tiapamil has additional pharmacological properties, which may contribute to its usefulness in the treatment of ventricular arrhythmias.